Monoglyceride Lipase (MGL) is a target known in the art and first identified by Wall et al. (Virus Res. 1997, 52, 152-167) in 1997 and designated HUKS. Dinh et al. (Proc. Nat. Acad. Sci., 2002, 99, 10819-10824) found that the rat MGL participates in inactivation of 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid monoglyceride. It is highly expressed in regions of rat brain that also express cannabinoid receptors and it appears to assume a presynaptic localization in the hippocampus. Adenovirus-mediated transfer of MGL cDNA into rat cortical neurons increased MGL expression and attenuated 2-AG accumulation induced by N-methyl-D-aspartate/carbachol. MGL inhibitors, on the other hand, have been shown by Schlossburg et al (Nat. Neurosci., 2010, Sep. 13(9), 1113-9) to enhance the signaling of the endocannabinoid system by elevating the level of 2-AG, the endocannabinoid of highest abundance in the central nervous system (CNS) and gastrointestinal tract. For this reason, MGL inhibitors are potentially useful for the treatment of pain, inflammation, and CNS disorders.
In addition to the brain, MGL is expressed in adipocytes, where it functions together with hormone-sensitive lipase (LIPE) to hydrolyze intracellular triglyceride stores, and in the intestine, where it is largely responsible for cleaving monoacyglycerols to form free fatty acids and glycerol. It has been observed by Chon, et al. (FASEB, 2008, 22, 807-12) that increased expression of MGL in the intestine causes an obese phenotype, most likely due to hyperphagia (overeating). Further evidence from MGL knockout mice (“MGL-ko mice”) (Taschler, et al. JBC, 2011, 286(20), 17467-77) showed that MGL-deficiency results in accumulation of 2-AG and other MG species in various tissues, including brain, adipose and liver. Fasted MGL-ko mice exhibited reduced plasma glycerol and triacylglycerol, as well as liver triacylglycerol levels indicative of impaired lipolysis. MGL-ko mice receiving a high-fat diet showed significantly improved glucose tolerance and insulin sensitivity in comparison to wild-type controls. These observations implicate MGL in metabolic diseases and suggest that MGL inhibitors will have beneficial effects on metabolic disorders, including obesity, hyperphagia and diabetes.
It is an object of the present invention to provide MGL inhibitors. It is also an object of the invention to provide a method of treating, ameliorating or preventing metabolic disorders, such as obesity, hyperphagia and diabetes, by the administration of a compound of formula (I). It is also an object of the invention to provide a method of reducing food consumption and/or weight gain of a subject, by the administration of a compound of formula (I). And, it is an object of the invention to provide a pharmaceutical composition comprising a compound of formula (I), useful for treating, ameliorating or preventing metabolic disorders.